title: Uric acid stimulates endothelin-1 gene expression associated with NADPH oxidase in human aortic smooth muscle cells.
abstract: OBJECTIVE
  Recent experimental and human studies have shown that hyperuricemia is associated with hypertension and cardiovascular diseases. Elevated levels of endothelin-1 (ET-1) has been regarded as one of the most powerful independent predictors of cardiovascular diseases. For investigating whether uric acidinduced vascular diseases are related to ET-1, the uric acid-induced ET-1 expression in human aortic smooth muscle cells (HASMC) was examined.
  
  
  METHODS
  Cultured HASMC treated with uric acid, cell proliferation and ET-1 expression were examined. Antioxidant pretreatments on uric acid-induced extracellular signal-regulated kinases (ERK) phosphorylation were carried out to elucidate the redox-sensitive pathway in proliferation and ET-1 gene expression.
  
  
  RESULTS
  Uric acid was found to increase HASMC proliferation, ET-1 expression and reactive oxygen species production. The ability of both N-acetylcysteine and apocynin (1-[4-hydroxy-3-methoxyphenyl]ethanone, a NADPH oxidase inhibitor) to inhibit uric acid-induced ET-1 secretion and cell proliferation suggested the involvement of intracellular redox pathways. Furthermore, apocynin, and p47phox small interfering RNA knockdown inhibited ET-1 secretion and cell proliferation induced by uric acid. Inhibition of ERK by U0126 (1,4-diamino-2,3-dicyano- 1,4-bis[2-aminophenylthio]butadiene) significantly suppressed uric acid-induced ET-1 expression, implicating this pathway in the response to uric acid. In addition, uric acid increased the transcription factor activator protein-1 (AP-1) mediated reporter activity, as well as the ERK phosphorylation. Mutational analysis of the ET-1 gene promoter showed that the AP-1 binding site was an important cis-element in uric acid-induced ET-1 gene expression.
  
  
  CONCLUSIONS
  This is the first observation of ET-1 regulation by uric acid in HASMC, which implicates the important role of uric acid in the vascular changes associated with hypertension and vascular diseases.
authors.affiliation: Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, China.
authors.forename: Hung-hsing
authors.initials: HH
authors.lastname: Chao
authors.forename: Ju-chi
authors.initials: JC
authors.lastname: Liu
authors.forename: Jia-wei
authors.initials: JW
authors.lastname: Lin
authors.forename: Cheng-hsien
authors.initials: CH
authors.lastname: Chen
authors.forename: Chieh-hsi
authors.initials: CH
authors.lastname: Wu
authors.forename: Tzu-hurng
authors.initials: TH
authors.lastname: Cheng
mesh_terms: D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D019255:NADPH Oxidases / Q000502:physiology*; D012313:RNA / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013268:Stimulation, Chemical; D014162:Transfection; D014527:Uric Acid / Q000494:pharmacology*
chemical_list: D019332:Endothelin-1; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014527:Uric Acid; D012313:RNA; D019255:NADPH Oxidases; D015500:Chloramphenicol O-Acetyltransferase; D048049:Extracellular Signal-Regulated MAP Kinases